1. Field of the Invention
The present invention is generally directed to novel bismethylene-17α carbolactones. More particularly, the invention is related to such derivatives having progestational and aldosterone antagonistic activity and methods of preparing and using these compounds.
2. Description of the Relevant Art
Many of the side effects associated with oral contraceptive pills and hormone replacement therapies are due to administration of hormones. Some of the potential side effects from contraceptives and hormone replacement therapies include: depression, vaginal discharge, changes in menstrual flow, breakthrough bleeding, nausea, vomiting, headaches, changes in the breasts, changes in blood pressure, loss of scalp hair, skin problems and skin improvements, increased risk of deep venous thrombosis (DVT) and pulmonary embolism, stroke, increased incidence of cancer, and myocardial infarction (heart attack). The incidence of various side effects appears to be related, to some extent, on the dosage of the progestogen and, in some cases, the estrogen components.
One of the most commonly used combined progestogens is 6β,7β,15β,16β-dimethylene-3-oxo-17α-pregn-4-ene-21,17-carbolactone (drospirenone). This compound is described in German Patent No. 3,022,337. Drospirenone, however, is only sparingly soluble in water at various pH values. The low aqueous solubility of drospirenone reduces its effectiveness due to poor bioavailability. For example, the absolute bioavailability of drospirenone from a single entity tablet is about 76%.
Other methylene-substituted-17α carbolactones have been reported to exhibit the combination of progestational and antialdosterone antagonistic activity. In EP 0 150 157, 6,6-ethylene-15,16-methylene carbolactones are described that exhibit a strong progestational and antialdosterone activity. EP 0 255 464 reports 2,2:6,6-diethylene-3-oxo-17α-pregn-4-ene 21,17-carbolactones having a stronger anti mineralcorticoid activity with a somewhat reduced progestational activity. As described in EP 0 150 157, these compounds are primarily suited for contraceptive use in women with cardiovascular risk factors such as obesity, age, smoking and elevated blood pressure.
Additionally, under acidic conditions (such as encountered in the gastric environment) 17α carbolactones (e.g., drospirenone) undergo isomerization to a form that is inactive. The combination of poor aqueous solubility and potential for isomerization makes the use of low dosage forms of 17α carbolactones difficult. This leads to the use of higher than necessary amounts of 17α carbolactones to counteract the inactivation and slow absorption of the active form.
The use of high dosages of a 17α carbolactones progestogen may lead to an increase in the occurrence of side effects. It is therefore desirable to develop 17α carbolactones progestogens that are highly effective for use in contraceptive and hormone replacement therapies, that are more resistant to the gastric environment, exhibit improved bioavailability, and/or reduce the incidence of side effects.